www.cityassays.org.uk

Rachel L Jones Principal Clinical Scientist

Therapeutic Drug Monitoring (TDM)

Overview

• Pharmacokinetics (PKs) • Pharmacogenomics (PGs) • Purpose of TDM • Criteria for TDM • Sampling requirements • Therapeutic range • Analytical methods • Specific drugs

PKs

PHARMACOKINETICS • Describes what the body does to drugs • Factors affecting concentration of drug in plasma

• “ADME” • Differs between individuals (inter-individual

variation) • Differs within an individual (intra-individual

variation)

PKs

(A) A D M E

(Adherence)

Absorption

Distribution

Metabolism

Elimination

PKs

Dose

prescribed

Dose taken Drug in

bloodstream

Drug at target

tissue (active

site)

Clinical

effect

Drug in other

tissues

Inactivated

Excreted

(A) A D

M E

E

(A)

ADHERENCE

• aka “compliance”

• Whether the patient actually takes the

drug they have been prescribed, or not

• Issues with chronic therapy

A

ABSORPTION • Amount of drug taken that actually reaches the

bloodstream • iv = 100% • oral = variable

• Depends on: • Drug formulation • Co-administered food / drugs • GI tract integrity / function • Genetic variability • First-pass metabolism

D

DISTRIBUTION • Once in the bloodstream, drugs are transported around

the body to the various tissues • Drug with either prefer to stay in the bloodstream or to

enter the body tissues

• Depends on:

• distribution:

• Relative solubility in fat or water • Binding to plasma proteins • Binding to tissue lipids

• Fat soluble • Plasma protein binding • Tissue lipid binding

M

METABOLISM • Process by which the body alters the chemical

structure of a compound

• Function:

• Location:

• N.B. Metabolism ≠ Inactiviation • Some drug metabolites are active

• Make drug more water-soluble • Enhance excretion

• Mainly in the liver (enzymes) • (Other tissues)

E

ELIMINATION • Removal of drugs from the body

• Routes:

• Kidney function very important • Reduced kidney function = reduced elimination

• Urine • Faeces

• Sweat • Breath • Breast milk • Hair • Nails • Placental transfer

Plasma drug levels

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DOSE

PEAK

TROUGH

(pre-dose) DOSING

INTERVAL

STEADY STATE: • Point of equilibrium • Rate of administration = Rate of elimination

HALF-LIFE (t1/2) • Time taken to reduce plasma concentration to

one-half of its initial value • t1/2 = dosing interval

(drugs usually administered once every t1/2) • Takes 5-7 x t1/2 to reach steady-state

Plasma drug levels

PGs

PHARMACOGENOMICS

• The role of genetics in drug response

• Describes how genetic variation alters PKs • ADME

• Predict how well a patient will respond to a drug regime based on their genetics

• “Personalised medicine”

PGs

FAST METABOLISERS

• Metabolise drugs quickly • May clear drugs before they have had time to work • May require higher doses

SLOW METABOLISERS

• Metabolise drugs slowly • Drug stays in body for longer = Efficacy • But potential for build-up of drug > MTC • Risk of toxicity • May require lower doses

PGs

EXAMPLE - TPMT

• …

Azathioprine 6-MP 6-TGN

6-MMP 6-MMP

6-TIMP

Purpose of TDM

ROBUST TDM PROGRAMME WILL ALLOW:

• Better patient management

• Improved patient quality of life

• Support compliance of medication

• Minimize toxicity

Indications

CRITERIA FOR TDM: 1. Narrow therapeutic index (therapeutic range) 2. Long-term therapy 3. Correlation between serum concentration and

clinical response 4. Variable pharmacokinetics

• Intra-individual • Inter-individual

5. Absence of suitable biomarker associated with therapeutic outcome

6. Co-administered with potentially interacting drugs

Therapeutic range

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MTC

MEC

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THERAPEUTIC

INDEX / RANGE

Therapeutic range

Represents the interval between:

• MEC – minimum effective concentration

• MTC – maximum therapeutic concentration

In optimal dosing: • Trough blood concentration should not fall below the

MEC • Peak blood concentration should not exceed the MTC

– minimum toxic concentration

Therapeutic range

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MTC

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THERAPEUTIC

RANGE UNDER-DOSING RISK OF TREATMENT FAILURE

Therapeutic range

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MEC

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THERAPEUTIC

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OVER-DOSING RISK OF TOXICITY

Therapeutic range

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THERAPEUTIC

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WIDE THERAPEUTIC RANGE TDM NOT REQUIRED

Therapeutic range

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THERAPEUTIC

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NARROW THERAPEUTIC RANGE TDM REQUIRED FOR OPTIMAL TREATMENT

Antibiotics

Different dosing regimes:

• Extended – e.g. once daily

• Frequent – e.g. 2-3x daily

• MIC – minimum inhibitory concentration

Antibiotics

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MTC

MIC

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EXTENDED DOSING

INTERVAL,

e.g. ONCE DAILY

TROUGH

(pre-dose)

Antibiotics

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MIC

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FREQUENT

DOSING INTERVAL,

e.g. 2-3x DAILY

PEAK

(1h post-dose)

TROUGH

(pre-dose)

Sample timing

PEAK

TROUGH

(pre-dose)

PEAK • Rarely used • Only for certain drugs in

specific circumstances

TROUGH • Recommended sampling time

for most drugs • Sample collected immediately

before next dose • Least intra- and inter-

individual variability • “Reference ranges” apply to

trough measurements

Sample timing

EXAMPLE: • …

Sample types

PLASMA / SERUM: • EDTA plasma • Plain serum • NO GEL TUBES • Lithium - NOT LITHIUMHEPARIN PLASMA!!!

WHOLE BLOOD: • e.g. For drugs found in RBCs, e.g. ciclosporin • EDTA

BLOODSPOT: • Home-sampling

Analytical Methods

METHODS FOR TDM

• Spectrophotometry / colorimetry

• Element analysis:

• Immunoassay:

• Chromatography: • HPLC (-UV / -DAD) • LC-MS/MS / LC-MS QToF • GC-MS

• EMIT • FPIA • CEDIA

• ISE • AAS • ICP-MS

Immunoassay

PROS • Readily automated • Rapid results • TAT, Throughput • Use existing routine chemistry analysers

CONS • Limited to repertoire provided by manufacturers • Not available for all (esp. new) drugs • Interference ( Specificity)

Chromatography

PROS • Sensitivity • Specificity • Simultaneous analysis of multiple compounds • Can work-up in-house methods

CONS • Require specialist equipment (£££) • Require technical expertise • TAT, Throughput

Chromatography

PROS • Sensitivity • Specificity • Simultaneous analysis of multiple compounds • Can work-up in-house methods

CONS • Require specialist equipment (£££) • Require technical expertise • TAT, Throughput

www.cityassays.org.uk

thanks for listening

any questions??

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